ORGANIC LETTERS
Synthesis of Substituted Imidazo[1,5-a]pyrazines via Mono-, Di-, and Directed Remote Metalation Strategies
2009 Vol. 11, No. 22 5118-5121
Johnathan Board,† Jian-Xin Wang,† Andrew P. Crew,*,‡ Meizhong Jin,‡ Kenneth Foreman,‡ Mark J. Mulvihill,‡ and Victor Snieckus*,† Department of Chemistry, Queen’s UniVersity, Kingston, Ontario, Canada K7L 3N6, and OSI Pharmaceuticals, Inc., 1 Bioscience Park DriVe, Farmingdale, New York 11735
[email protected];
[email protected] Received August 13, 2009
ABSTRACT
Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a-2g (Table 1), and 4a-4d (Table 2). Under similar conditions, the C3-methyl derivatives 2a and 5 undergo surprising regioselective C5-deprotonation to afford, after electrophile quench, products 4b and 6a-6p (Table 3), results that are rationalized by quantum mechanical calculations. Benzamide 7b, obtained from such metalation chemistry followed by Suzuki cross coupling, undergoes directed remote metalation-cyclization to afford 8, representing the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one tricyclic ring system.
We have recently reported1 the first palladium catalyzed Heck-type direct substitution reaction on the π-deficient pyrazine ring of the imidazo[1,5-a]pyrazine framework (Figure 1A). The dearth of knowledge concerning metalation reactivity of this and related ring systems stimulated our
interest to undertake a systematic study to contribute to the signficant area of carbanionic heteroaromatic chemistry.2 Herein we report results which demonstrate (a) regioselective mono- as well as dimetalation of derivative 1 (Figure 1C) and (b) C5 metalation of the C3-methyl derivative (Figure 1B), both leading to new imidazo[1,5-a]pyrazine derivatives
†
Queen’s University. OSI Pharmaceuticals, Inc. (1) Wang, J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill, M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923. ‡
10.1021/ol901889e CCC: $40.75 Published on Web 10/20/2009
2009 American Chemical Society
(2) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. AdV. Heterocycl. Chem. 1991, 52, 187. Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4489.
which provide considerable potential for further manipulation of this heterocyclic ring system. In addition, we establish a new illustration of the directed remote metalation (DreM) concept3 on the Suzuki-derived heterobiaryl 7 leading to the new heterocyclic 2,5,11c-triazadibenzo[cd,f]azulen-7(6H)one framework 8. These results constitute the first investigation of carbanionic chemistry on the imidazo[1,5-a]pyrazine ring system which is of current interest in the development of new antimicrobial, cardiovascular, and antitumor drugs4 and which also portends broader significance for synthetic studies for this and related heterocyclic systems.
Table 1. Synthesis of 3-Substituted 8-Chloroimidazo[1,5-a]pyrazines 2a-2g
1 2 3 4 5 6 7 8
Figure 1. The direct Heck and Suzuki-Miyaura reaction sites (A) and observed metalation sites (B, C) for imidazo[1,5-a]pyrazines.
To initiate this study, the readily accessible5 8-chloroimidazo[1,5-a]pyrazine 1 was subjected to reaction with nBuLi (1 equiv) and quenched with various electrophiles to afford exclusively C3-substitution products 2a-2g (Table 1). Reactions with carbon electrophiles at three oxidation states (entries 1-6) and iodine (entry 8) proceeded uneventfully whereas that with TMSCl failed, an observation which may be due to product instability, related to the known lability of the imidazole C2-Si bond.6 Efforts then turned to investigating the potential for dimetalation of this heterocyclic core and for the sequential (3) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206. (4) Examples of such biological applications are: IGF-IR inhibitors, for example: (a) Mulvihill, M. J.; Ji, Q.-S.; Coate, H. R.; Cooke, A.; Dong, H.; Feng, L.; Foreman, K.; Rosenfeld-Franklin, M.; Honda, A.; Mak, G.; Mulvihill, K. M.; Nigro, A. I.; O’Connor, M.; Pirrit, C.; Steinig, A. G.; Siu, K.; Stolz, K. M.; Sun, Y.; Tavares, P. A. R.; Yao, Y.; Gibson, N. W. Bioorg. Med. Chem. 2008, 16, 1359. c-SRC inhibition and treatment of acute ischemic stroke: (b) Mukaiyama, H.; Nishimura, T.; Kobayashi, S.; Ozawa, T.; Kamada, N.; Komatsu, Y.; Kikuchi, S.; Oonota, H.; Kusama, H. Bioorg. Med. Chem. 2007, 15, 868. Corticotropin releasing hormone receptor ligands: (c) Hartz, R. A.; Gilligan, P. J.; Nanda, K. K.; Tebben, A. J.; Fitzgerald, L. W.; Miller, K. Bioorg. Med. Chem. Lett. 2002, 12, 291. (5) Initial syntheses of imidazo[1,5-a]pyrazines: (a) Abushanab, E.; Bindra, A. P.; Goodman, L.; Peterson, H., Jr. J. Org. Chem. 1973, 38, 2049. (b) Abushanab, E.; Bindra, A. P.; Lee, D. Y.; Goodman, L. J. Heterocycl. Chem. 1975, 12, 211. (c) Abushanab, E.; Bindra, A. P.; Goodman, L. J. Heterocycl. Chem. 1975, 12, 207. (d) Abushanab, E.; Bindra, A. P.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 3373. (e) Abushanab, E.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 3376. (f) Abushanab, E.; Lee, D. Y.; Goodman, L. J. Org. Chem. 1975, 40, 33792. Syntheses of more highly substituted imidazo[1,5-a]pyrazines: (g) Albert, A.; Ohta, K. J. Chem. Soc. (C) 1970, 11, 1540. (h) Davey, D. D. J. Org. Chem. 1987, 52, 4379. (I) Chattopadhyay, G.; Ray, S. J. Chem. Res. Synop. 1992, 5, 170. (j) Marchand, E.; Morel, G. Tetrahedron Lett. 1993, 34, 2319. (k) Trcˇek, T.; Meden, A.; Vercˇek, B. Synlett 2000, 10, 1458. (l) Eltsov, O. S.; Mokrushin, V. S.; Tkachev, A. V. Russ. Chem. Bull., Int. Ed. 2004, 53, 2293. (m) Trcˇek, T.; Vercˇek, B. Synthesis 2006, 20, 3437. (n) Mulvihill, K. M.; Castelhano, A. L. US Patent 2007/0129547 A1. Org. Lett., Vol. 11, No. 22, 2009
EX
R1
product (%)a
MeI DMF 4-MeOC6H4C(O)H Mesitaldehyde CO2 ClCONEt2 ClSiMe3 I2
Me CHO 4-MeOC6H4CHOH MesCHOH CO2Me Et2NCO H I
2a (70)b 2b (72) 2c (74) 2d (83) 2e (86)c 2f (65) n.r.d 2g (78%)
a Yield of isolated material. b Purified by supercritical fluid chromatography to remove bis-Me byproduct. c Isolated as the methyl ester due to purification difficulties. d No reaction as confirmed by 1H NMR of the recovered material.
introduction of various electrophiles. Compound 1 was treated with 2.3 equiv of nBuLi (optimal conditions) followed by quench with 2.5 equiv of several electrophiles to give C3/C5-disubstituted imidazopyrazines 4a-4d in moderate to excellent yields (Table 2). The formation of product with high deuterium incorporation (entry 1) constitutes evidence for the intermediacy of the dilithiated species 3.7 Consistent with the observation of Table 1, entry 7, quench with 2.5 equiv of TMSCl gave only the C5-silylated product 4d in moderate yield, presumably owing to the derived C3-TMS derivative instability. Nevertheless, this result remains of value since it potentially offers access to other C5 analogues, either directly through ipso-desilylation8 or through Hiyama type crosscoupling chemistries via C5 siloxanes or fluorosilanes.9 In view of the selective C3 over C5 kinetic anion reactivity established by the results of Table 1, we tested the thereby expected greater nucleophilic reactivity at the C5 site of the dianion 3.10 Thus, treatment of 1 with 2 equiv of nBuLi11 followed by 1 equiv of iodine or CD3OD initially provided evidence of selectivity; however, subsequent results were inexplicably inconsistent giving ratios between 4:1 and 1:8 of C5:C3 products within the same batch of reactions, and despite close control of the various reaction variables.12 With the results of studies on compound 1 in hand, we turned our attention to the metalation of the equally accessible5 8-chloro-3-methylimidazo[1,5-a]pyrazine 2a. In contrast to expectation,13 treatment of 2a with 1.1 equiv (6) The N-protected imidazole C2-TMS system is moderately unstable towards nucleophilic attack at silicon even when generated in situ, and its isolation can be highly problematic due to hydrolysis: Carpenter, A. J.; Chadwick, D. J. Tetrahedron 1986, 42, 2351. 5119
Table 2. Synthesis of C3/C5 Disubstituted 8-Chloroimidazo[1,5-a]pyrazines 4a-4d
R1
EX
R2
1 2 3
CD3OD MeI Cl2
D Me Cl
D Me Cl
4
ClSiMe3
SiMe3
H
a
Table 3. Synthesis of 5-Substituted 8-Chloro-3-methylimidazo[1,5-a]pyrazines 4b and 6a-6p
product (%)a 4a (94) 4b (82) 4c (62) 4d (48)c
b
Yield of isolated material. 86% deuterium incorporation as determined by integration of the appropriate signals in the 1H NMR spectrum. c Average of two independent reactions.
of nBuLi and subsequent reaction with methyl iodide afforded the C5-methylated product 4b in excellent yield (entry 1, Table 3). Similarly, and usually with greater efficacy than the reactions of compound 1 (Table 1), compound 2a underwent reaction with other carbon (entries 2-7), silicon (entry 8), and halogen (entries 9-12) electrophiles to afford C5-substituted products 6a-6i in good to excellent yields. To extend the scope of the reaction, the C8-methoxy derivative 5 was subjected to the same metalation/quenching conditions to provide similarly synthetically useful yields of products 6j-6p (entries 13-20). Quantum calculations on compound 2a suggest that the approximate difference in pKa values are in accord with the observation of C5 over C3-methyl deprotonation. Figure 2a shows the calculated partial charges on the carbons bound to the most acidic protons, with more electron richness on the carbons correlating with a lower absolute calculated pKa. Use of perturbative methods has previously successfully predicted unexpected lithiation sites14 and its application here confirms the predictions from the more approximate pKa calculation. Figure 2b shows the calculated Fukui indices, with values closer to 1 indicating, in this case, a greater proclivity to undergo (7) For previous work on benzamide dianions, see: Mills, R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett. 1985, 26, 1145. (8) Zhao, Z.; Jaworski, A.; Piel, I.; Snieckus, V. Org. Lett. 2008, 10, 2617. (9) Denmark, S. E.; Sweis, R. F. Metal-Catalysed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 1, Chapter 4, p 163. (10) For successful results of such an expectation in furan and thiophene amide directed ortho metalation derived dianions, see: Doadt, E. G.; Snieckus, V. Tetrahedron Lett. 1985, 26, 1149. (11) An investigation of bases, nBuLi, KOtBu, MeMgBr, EtMgBr, and i PrMgBr:LiCl, showed that only the use of nBuLi led to the formation of the dianion. Interestingly, although normal Grignard reagents were insufficiently basic to form the dianion, application of iPrMgBr:LiCl led exclusively to the formation of the C3 monoanion, as established by I2 quench experiment, even when excess base was used. 5120
EX
X
R1
product (%)a
MeIb DMF 4-O2NC6H4CHO 4-MeOC6H4CHO Mesitaldehyde CO2 ClCONEt2 ClSiMe3 Cl3CCCl3 CBr4 Br2 I2 MeI DMF 4-MeOC6H4CHO Mesitaldehyde CO2 ClCONEt2 ClSiMe3 I2
Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl OMe OMe OMe OMe OMe OMe OMe OMe
CH3 CHO; ClfNMe2 4-O2NOC6H4CHOH 4-MeOC6H4CHOH MesCHOH CO2H Et2NCO SiMe3 Cl Br Br I Me CHO 4-MeOC6H4CHOH MesCHOH CO2Mef Et2NCO SiMe3 I
4b (91) 6a (79)c 6b (83) 6c (84)d 6d (87) 6e (quan) n.r.e 6f (81) 6g (98) 6h (59) 6h (74) 6i (quan) 6j (65) 6k (77) 6l (76)d 6m (62) 6n (64)f n.r.e 6o (70)d 6p (79)
b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
a Yield of isolated material. b Sequential addition of 2 portions of 1.2 equiv of MeI. c Isolated as the C-8 dimethylamino analogue due to unavoidable nucleophilic displacement of Cl by NMe2. d Average of two independent reactions. e No reaction as confirmed by 1H NMR of the recovered starting material. f Isolated as the methyl ester due to purification difficulties.
lithiation. Both calculations are in accord with the experimentally observed C5 lithiation of 2a.15
Figure 2. Key calculated properties for 8-chloro-3-methylimidazo[1,5-a]pyrazine 2a at potential reactive sites. (a) Partial charges on the molecule. (b) Fukui indices for the LUMO of the molecule.
The knowledge that remote lateral metalation of vinylogously acidic 2′-methylbiaryl-2-amides to give phenanthrols may be achieved3,16 suggested that compound 7 (Scheme Org. Lett., Vol. 11, No. 22, 2009
Scheme 1. Directed Remote Metalation-Cyclization Route to the Triazadibenzo[cd,f]azulen-7(6H)-one 8
1) may provide similar reactivity at the enhanced acidic C3methyl site to afford cyclized products. To this end, compound 7b, readily prepared from compound 6p via a Suzuki coupling with 2-(diethylcarbamoyl)phenylboronic acid,17 was treated at -78 °C with preformed LiTMP (3 equiv) and was observed to undergo cyclization to give the triazadibenzo[cd,f]azulen-7(6H)-one 8 in modest yield.18,19 The methylene 1H NMR signal at δ ) 4.48 ppm for compound 8 is clear evidence for the ketonic structure shown. (12) See Supporting Information. (13) Strong base deprotonation of N-protected-2-methylimidazole (Iddon, B.; Ngochindo, R. I. Heterocycles 1994, 11, 2487.) most 2-methylheteroaromatics, (e.g. 2-picoline with NaNH2, see Kantlehner, W.; Kapassakalidis, J. J. Synthesis 1981, 6, 480. with LDA, see Bhasin, K. K.; Singh, J.; Singh, K. N. Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 597. with nBuLi, see Andrews, I. P; Lewis, N. J.; McKillop, A.; Wells, A. S. Heterocycles 1996, 43, 1151.) usually occurs at the alkyl group. (14) Ayers, P. W.; Anderson, J. S. M.; Bartolotti, L. J. Int. J. Quantum Chem. 2004, 101, 520. (15) The general applicability of this approach to predict metalation sites is being actively explored.
Org. Lett., Vol. 11, No. 22, 2009
In conclusion, we have demonstrated useful and convenient metalation routes for the synthesis of C3- and C3/C5derived 8-substituted imidazo[1,5-a]pyrazines 2a-2g, 4a-4d, and 6a-6p. Such substitutions serve as functional handles for further derivatization of this privileged and biologically significant heterocyclic scaffold. Furthermore, adaption of the directed remote metalation (DreM) concept, as yet sparsely investigated within heterocyclic frameworks,3 on the imidazo[1,5-a]pyrazine 7 has afforded the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one 8. The considerably extended scope of this imidazo[1,5-a]pyrazine metalation chemistry over that of the imidazo[1,2-a]pyrazine system,20 together with the DFT calculations, provides new insight into the carbanionic reactivity of this less common heterocycle and may be of value for synthesizing heterocycles of greater complexity. Further investigations on the DreM chemistry leading to the new heterocyclic scaffold 8 are in progress. Acknowledgment. We gratefully acknowledge OSI Pharmaceuticals, Inc. for a grant to V.S. in support of this work. Dr. Ruiyao Wang of Queen’s University is warmly thanked for prompt solution of the X-ray crystal structure of compound 8 and for his enthusiastic interest. Supporting Information Available: Experimental procedures and characterization data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OL901889E (16) Fu, J.-M.; Snieckus, V. Can. J. Chem. 2000, 78, 905. (17) Zhao, Z.; Snieckus, V. Org. Lett. 2005, 7, 2523. (18) The structure was confirmed by single crystal X-ray analysis, see Supporting Information. (19) Under the same reaction conditions, the C8-Cl analogue 7a gave only a chromatographically inseparable mixture (silica gel flash chromatography) of at least three compounds, presumably due to complications, in part, resulting from the greater reactivity of the C8-Cl over C8-OMe group. (20) Generation of an imidazo[1,2-a]pyrazine dilithiated species, as evidenced by the formation of dideuterated product upon DCl quench, has been previously reported, see: Vitse, O.; Bompart, J.; Subra, G.; Viols, H.; Escale, R.; Chapat, J. P.; Bonnet, P. A. Tetrahedron 1998, 54, 6485.
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